Role of excitatory amino acids in antagonist-precipitated morphine and clonidine withdrawal

Excitatory amino acid (EAA) projections in the locus coeruleus (LC) have been implicated in the genesis of opioid physical dependence (1,2). Since both opioids and a₂-agonists produce similar depressant effects on LC activity and demonstrate withdrawal syndromes following antagonist challenge (3,4), an increase in the activity of these pathways might be involved in the development of morphine and clonidine withdrawal syndromes. Using differential normal pulse voltammetry (DNPV), the role of EAA mechanisms in LC responses elicited during antagonist-precipitated morphine and clonidine withdrawal was examined. Intracerebroventricular (icv) injection of morphine or clonidine produced a marked decrease in the catechol oxidation current (CA·OC) recorded from LC in halothane anaesthetized rats. Challenge with the opioid antagonist naloxone and a₂-adrenoceptor antagonist atipamezole (5), given forty-five minutes after morphine and clonidine respectively, produced rebound increases in CA·OC in the LC. These rebound responses were blocked by pretreatment with EAA receptor antagonists γ-D-glutamyl-glycine (DGG) or (-)-2-amino-7-phosphonoheptanoic acid (D-APH). Pretreatment with DGG or D-APH also blocked the naloxone-precipitated rebound increase in CA·OC in the LC of morphine dependent animals. These data suggest that the activation of EAA pathways contribute to the genesis of LC hyperactivity during antagonist-precipitated withdrawal following morphine or clonidine treatment.